SY03-4
THE ENDOGENOUS OPIOID SYSTEM: DYSREGULATION IN THE STRIATUM OF HUMAN ALCOHOLICS

Extract

The endogenous opioid peptides dynorphins and enkephalins may be involved in brain-area specific synaptic adaptations relevant for different stages of an addiction cycle. We compared the levels of prodynorphin (PDYN) and proenkephalin (PENK) mRNAs (by qRT-PCR), and dynorphins and enkephalins (by radioimmunoassay) in the caudate nucleus and putamen between alcoholics and control subjects. We also evaluated whether PDYN promoter variant rs1997794 associated with alcoholism affects PDYN expression. Postmortem specimens obtained from 24 alcoholics and 26 controls were included in final statistical analysis. PDYN mRNA and Met-enkephalin-Arg-Phe, a marker of PENK were downregulated in the caudate of alcoholics, while PDYN mRNA and Leu-enkephalin-Arg, a marker of PDYN were decreased in the putamen of alcoholics carrying high risk rs1997794 C allele.

Analysis of epigenetic mechanism underlying alterations in PDYN transcription identified a locus-specific repressive DNA methylation as mechanism controlling neuron-specific transcription of this gene in the human brain. A novel function was unraveled for short PDYN CpG island that may act as a single nucleosome-size chromatin element on which environmental and cellular signals converge and regulate transcription through coherent changes in CpG methylation. This mechanism contributes to neuron and glia specific gene expression and is affected in pathological brain. Epigenetic dysregulation of opioid genes may contribute to changes in goal directed behavior and formation of a compulsive habit in alcoholics. Supported by the Swedish FAS, FORMAS and VR.